US20180325854A1 - Use of proteasome inhibitors to treat ocular disorders - Google Patents

Use of proteasome inhibitors to treat ocular disorders Download PDF

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Publication number
US20180325854A1
US20180325854A1 US15/773,920 US201615773920A US2018325854A1 US 20180325854 A1 US20180325854 A1 US 20180325854A1 US 201615773920 A US201615773920 A US 201615773920A US 2018325854 A1 US2018325854 A1 US 2018325854A1
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eye
ocular
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proteasome inhibitor
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Richard Coulon
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Accuitis Pharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue

Definitions

  • the invention is generally in the area of treatment of ocular disorders, particularly ocular disorders mediated by proteasomes, and specifically including ocular inflammation, infections of the eye, and ocular disorders caused by inflammation and/or bacterial infections in the eye.
  • the ubiquitin-proteasome system is the main intracellular pathway for modulated protein turnover, playing an important role in the maintenance of cellular homeostasis. It also exerts a protein quality control through degradation of oxidized, mutant, denatured, or misfolded proteins, and is involved in many biological processes where protein level regulation is necessary. This system allows the cell to modulate its protein expression pattern in response to changing physiological conditions and provides a critical protective role in health and disease.
  • Impairments of UPS function in the central nervous system underlie a number of genetic and idiopathic diseases, many of which affect the retina.
  • the relationship between UPS dysfunction is associated with numerous retina-specific illnesses with UPS involvement, such as retinitis pigmentosa, macular degenerations, glaucoma, diabetic retinopathy (DR), and aging-related impairments.
  • DR diabetic retinopathy
  • the ubiquitin-proteasome system (UPS) and autophagy are the two major intracellular protein degradation systems, and work collaboratively in many biological processes including development, apoptosis, aging, and countering oxidative injuries.
  • proteasome inhibitors have been shown to increase the protein levels of autophagy-specific genes Atg5 and Atg7, and to enhance the conversion of microtubule-associated protein light chain (LC3) from LC3-I to its lipidative form, LC3-II.
  • proteasome inhibitors can confer resistance to oxidative injury by a pathway involving inhibition of the PI3K-Akt-mTOR pathway and activation of autophagy.
  • Proteasome inhibitors can also block development of posterior capsular opacification (PCO), and can also activate autophagy by inhibiting the PI3K-Akt-mTOR pathway as an anti-oxidation defense in human RPE cells.
  • PCO posterior capsular opacification
  • TNF-alpha, IL-1beta, and TII induce expression of proinflammatory cytokines and ICAM-1 in hRPE cells through an NF-kappaB-dependent signal transduction pathway.
  • This effect can be blocked by administration of a proteasome inhibitor, by preventing I kappaB degradation.
  • Inhibition of NF-kappaB can also be a useful strategy to treat proliferative vitreoretinopathy and uveitis, ocular diseases initiated and perpetuated by cytokine activation, and is also constitutively active in human retinoblastoma cells and promotes their survival.
  • Proteasome inhibitors can also induce apoptosis in human retinoblastoma cell lines, and as such, can also be used to treat retinoblastoma (see Invest Ophthalmol Vis Sci. 2007; 48(10):4706-19).
  • Proteasome inhibitors also provide protective effects in connection with ischemia-reperfusion injury in the retina. This effect is believed to be due to inhibition of the activation of NF- ⁇ B related to IR insult, and reducing the inflammatory signals and oxidative stress in the retina.
  • Ocular disorders associated with inflammation including ocular rosacea, dry eye, meibomian gland dysfunction/disease, posterior blepharitis, geographic atrophy, dry age related macular degeneration, wet age related macular degeneration, diabetic retinopathy, diabetic macular edema, uveitis, ulceris, ocular injuries resulting from inflammation following eye surgeries, and inflammation caused by eye infections, whether by bacterial, viral, or other microbiological agents.
  • Ocular injury is frequently associated with the inflammation caused by the immune response to the infection.
  • Common eye infections include conjunctivitis (pink eye), blepharitis, trachoma and trichiasis, and these infections can affect any part of the eyes, from the eye lids to the cornea, and even the optic nerves in the back of the eye.
  • compositions and methods for treating ocular disorders including those associated with the ubiquitin-proteasome system (UPS), or with the production of pro-inflammatory cytokines.
  • UPS ubiquitin-proteasome system
  • present invention provides such compositions and methods.
  • the present invention is based, in part, on the discovery that hydrocinnamate compounds that exhibit proteasome modulation activity, and in particular, proteasome inhibitory activity, can be used to topically or systemically treat ocular disorders associated with proteasome activity.
  • the hydrocinnamate compounds can be applied to the eye, in any of a variety of ocular formulations, to treat ocular disorders such as ocular rosacea.
  • the hydrocinnamate compounds can also be administered systemically to treat ocular disorders.
  • compositions include a cinnamate or dihydrocinnamate compound with proteasome inhibitor activity.
  • proteasome inhibitors compounds have one of the following formulas:
  • W is selected from the group consisting of a methyl group, an alkyl group, a methylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom
  • X 1 to X 5 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, an alkyl group, an aryl group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is an ester of a dihydrocinnamate; or
  • compositions can further include appropriate carriers for optical administration, and the compositions can be used to treat or prevent the ocular disorders described herein.
  • compositions include oral dosage forms, eye drops, gels, ointments, and other topically applied formulations, ocular inserts, formulations for injection, and formulations designed for iontophoretic administration.
  • the compositions are in the form of stabilized formulations (i.e., formulations which not require reconstitution with separately supplied sterile water), and in other embodiments, are in the form of formulations for reconstitution.
  • oral dosage forms are used.
  • the present invention further relates to stabilized aqueous proteasome inhibitor formulations.
  • the stabilized formulations do not require reconstitution with separately supplied sterile water, aqueous solutions, or aqueous suspensions.
  • Such stabilized formulations can be administered to the eye either prophylactically or to treat the disorders discussed herein.
  • the ophthalmic formulations include water and proteasome inhibitor; and preferably have a pH in the range of between about 4.0 and about 7.0, more preferably from a pH of about 6.0 to about 7.5.
  • the formulations can further include between about 0.4% and about 1.0% sodium chloride; between about 0.1% and about 2.0% citric acid; between about 0.1% and about 2.0% sodium citrate, between about 0.1% and about 10.0% proteasome inhibitor; and water.
  • compositions can also include a lightly crosslinked carboxyl-containing polymer, which causes the solution to undergo a rapid increase in viscosity upon a pH rise associated with administration to tissues, such as those of the eye and the surrounding region.
  • a depot of proteasome inhibitor can be placed in contact with the eye for a sufficient length of time to allow a sufficient concentration of the proteasome inhibitor to diffuse into the cells of the targeted eye tissue(s).
  • a therapeutically effective concentration of the proteasome inhibitor will remain in the tissue(s) for a considerable period. Accordingly, an advantage of certain preferred forms of the present invention is a simplified dosing regimen.
  • a proteasome inhibitor-containing depot can be formed by several means.
  • One method of forming the depot involves including lightly crosslinked carboxyl containing polymers to the ophthalmic formulations, which causes the solutions to undergo a rapid increase in viscosity upon a pH rise associated with administration to tissues such as those of the eye and surrounding region.
  • a depot of the proteasome inhibitor can alternatively be formed by injecting a bolus of the composition into a target tissue.
  • the injection is intended to form a depot of material within the sclera, to accommodate extended release of the material to the surrounding tissues.
  • Inserts placed under the eyelid have been used, for example, to deliver therapeutics to the ocular and periocular region.
  • compositions can comprise one or more additional active agents.
  • additional active agents include, but are not limited to, anesthetics, anti-inflammatory agents, antimicrobial/anti-infective agents, anti-proliferative agents and combinations thereof.
  • the formulations described herein can be administered to the eye to treat disorders mediated by proteasomes, and/or which have an inflammatory component.
  • the formulations are applied to an eye in an amount effective to treat or prevent the disorders.
  • the formulations can also provide anesthesia, prevent or treat inflammation, prevent unwanted cell proliferation and/or to provide treatment or prophylaxis of microbial infections.
  • compositions including one or more proteasome inhibitor, and also optionally including an anti-inflammatory agent include ocular rosacea, wet and dry age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, neovascular glaucoma, retinal vasculitis, uveitis, such as posterior uveitis, keratoconjunctivitis sicca, conjunctivitis, retinitis secondary to glaucoma, neovascular glaucoma, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, ocular inflammation following ocular surgery, ocular inflammation resulting from physical eye trauma, cataract, ocular allergy, dry eye, blepharitis, meibomian gland dysfunction, neurodegenerative disorders affecting the retina, including Alzheimer's, Parkinson'
  • prophylaxis can include prevention of post-surgical infection, and minimization of post-surgical inflammation.
  • Representative types of eye surgeries for which the compositions can be used to provide anesthesia include laser eye surgery, refractive surgery, keratoplasty, keratotomy, keratomilleusis, cataract surgery, glaucoma surgery, canaloplasty, Karmra inlays, scleral reinforcement surgery, corneal surgery, vitreo-retinal surgery, retinal detachment repair, retinopexy, eye muscle surgery, surgery involving the lacrimal apparatus, insertion of implants into the eye, and eye removal.
  • Representative microbial infections that can be treated or prevented using combinations of the proteasome inhibitors and a suitable antimicrobial agent include viral, fungal, and bacterial infections in the eye, as well as ocular disorders resulting from these infections, such as trachoma, conjunctivitis, and the like.
  • Representative bacteria that cause ocular infections in the inner or external eye include Haemophilus, Neisseria, Staphylococcus, Streptococcus , and Chlamydia.
  • anti-inflammatory agents and antimicrobials i.e., antivirals, antibacterials, antifungals, antiparasitics, and the like
  • antimicrobials i.e., antivirals, antibacterials, antifungals, antiparasitics, and the like
  • Other active agents such as anti-proliferatives, anti-metabolites, VEGF inhibitors, prostaglandins, TGF-beta, mitomycin C, and antioxidants can also be added.
  • the invention described herein relates to compositions and methods for using proteasome inhibitors to treat ocular disorders, including those mediated by proteasomes, those associated with an inflammatory component, and those associated with infections, including viral, bacterial, fungal, and parasitic ocular infections.
  • the proteasome inhibitor can be administered alone or in combination with one or more additional active agents.
  • the additional active agent can be an antibiotic, and where the disorder is associated with inflammation, or the patient has eye surgery which can result in inflammation, the additional active agent can be an anti-inflammatory agent.
  • an effective amount refers to the amount of proteasome inhibitor, alone or in combination with one or more antibiotics, needed to eradicate the ocular infection, and/or, in combination with an anti-inflammatory agent, to eradicate the bacterial cause and inflammatory symptoms associated with various ocular disorders.
  • administering is meant a method of giving one or more unit doses of an antibacterial pharmaceutical composition to an animal (e.g., topical, oral, intravenous, intraperitoneal, or intramuscular administration).
  • the method of administration may vary depending on various factors, e.g., the components of the pharmaceutical composition, site of the potential or actual bacterial infection, bacteria involved, and severity of the actual bacterial infection.
  • bacteria is meant a unicellular prokaryotic microorganism that usually multiplies by cell division.
  • ocular bacterial infection is meant the invasion of an eye in a host animal by pathogenic bacteria.
  • the infection may include the excessive growth of bacteria that are normally present in or on the body of an animal or growth of bacteria that are not normally present in or on the animal.
  • a bacterial infection can be any situation in which the presence of a bacterial population(s) is damaging to a host animal.
  • an animal is “suffering” from an ocular bacterial infection when an excessive amount of a bacterial population is present in or on the animal's eye, or when the presence of a bacterial population(s) is damaging the cells or other tissue in the eye of the animal.
  • Persistent bacterial infection is meant an infection that is not completely eradicated through standard treatment regimens using antibiotics.
  • Persistent bacterial infections are caused by bacteria capable of establishing a cryptic phase or other non-multiplying form of a bacterium and may be classified as such by culturing bacteria from a patient and demonstrating bacterial survival in vitro in the presence of antibiotics or by determination of anti-bacterial treatment failure in a patient.
  • Trachoma is an example of a persistent ocular bacterial infection.
  • a persistent infection in a patient includes any recurrence of an infection, after receiving antibiotic treatment, from the same species more than two times over the period of two or more years or the detection of the cryptic phase of the infection in the patient.
  • An in vivo persistent infection can be identified through the use of a reverse transcriptase polymerase chain reaction (RT-PCR) to demonstrate the presence of 16S rRNA transcripts in bacterially infected cells after treatment with one or more antibiotics (Antimicrob. Agents Chemother. 12:3288-3297, 2000).
  • RT-PCR reverse transcriptase polymerase chain reaction
  • Ocular viral infections include common pink eye, ocular herpes, which occurs with exposure to the Herpes simplex virus, shingles, and Ebola, which persists in the eye.
  • Ocular fungal infections include fungal keratitis, which is often associated with Fusarium fungi.
  • Acanthamoeba keratitis and river blindness are examples of parasitic ocular infections.
  • chronic disease is meant a disease that is inveterate, of long continuance, or progresses slowly, in contrast to an acute disease, which rapidly terminates.
  • a chronic disease may begin with a rapid onset or in a slow, insidious manner but it tends to persist for several weeks, months or years, and has a vague and indefinite termination.
  • immunocompromised is meant a person who exhibits an attenuated or reduced ability to mount a normal cellular or humoral defense to challenge by infectious agents, e.g., viruses, bacterial, fungi, and protozoa.
  • infectious agents e.g., viruses, bacterial, fungi, and protozoa.
  • Persons considered immunocompromised include malnourished patients, patients undergoing surgery and bone narrow transplants, patients undergoing chemotherapy or radiotherapy, neutropenic patients, HIV-infected patients, trauma patients, burn patients, patients with chronic or resistant infections such as those resulting from myelodysplastic syndrome, and the elderly, all of who may have weakened immune systems.
  • inflammatory disease is meant a disease state characterized by (1) alterations in vascular caliber that lead to an increase in blood flow, (2) structural changes in the microvasculature that permit the plasma proteins and leukocytes to leave the circulation, and (3) emigration of the leukocytes from the microcirculation and their accumulation in the focus of injury.
  • the classic signs of acute inflammation are erythema, edema, tenderness (hyperalgesia), and pain.
  • Chronic inflammatory diseases are characterized by infiltration with mononuclear cells (e.g., macrophages, lymphocytes, and plasma cells), tissue destruction, and fibrosis.
  • Non-limiting examples of inflammatory ocular diseases include ocular rosacea, trachoma, wet and dry age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, neovascular glaucoma, retinal vasculitis, uveitis, such as posterior uveitis, conjunctivitis, retinitis secondary to glaucoma, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, ocular inflammation following ocular surgery, ocular inflammation resulting from physical eye trauma, cataract, ocular allergy and dry eye.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • glaucoma neovascular glaucoma
  • retinal vasculitis uveitis
  • uveitis such as posterior uveitis, conjunctivitis, retinitis secondary to glaucoma
  • treating is meant administering a pharmaceutical composition for prophylactic and/or therapeutic purposes.
  • To “prevent disease” refers to prophylactic treatment of a patient who is not yet ill, but who is susceptible to, or otherwise at risk of, a particular disease.
  • To “treat disease” or use for “therapeutic treatment” refers to administering treatment to a patient already suffering from a disease to improve the patient's condition.
  • treating is the administration to a mammal either for therapeutic or prophylactic purposes.
  • pharmaceutically acceptable salt is used throughout the specification to describe any pharmaceutically acceptable salt form of the proteasome inhibitors described herein.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Citric acid is a specific example of a suitable acid.
  • Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
  • Pharmaceutically acceptable salts include also include complexes with amines, including ammonia, primary, secondary and tertiary amines.
  • the amines can form salts or partial salts with one or more of the phenolic hydrogens.
  • the present invention satisfies an existing need for compounds that effective in treating ocular disorders mediated by proteasomes, or associated with inflammation.
  • compositions include a proteasome inhibitor of the formulas:
  • W is selected from the group consisting of a methyl group, an alkyl group, a methylene group, an amine group, an acyl group, a carbonyl group, an oxygen atom, a sulfur atom
  • X 1 to X 5 are independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, an ether group, an alkyl group, an aryl group, a nitro group, a cyano group, a thiol group, a thioether group, an amino group, an amido group, and an OR group, where R is an ester of a dihydrocinnamate; or
  • HSA human serum albumin
  • ionizable groups 116 total acidic groups (98 carboxyl and 18 phenolic OH) and 100 total basic groups (60 amino, 16 imidazolyl, and 24 guanidyl).
  • These complexes can be formed by mixing the compounds with albumin, or by complexing albumin with the compounds described herein using a multivalent cation. Multivalent cations can, for example, can bridge phenolic groups on the compounds described herein, and phenolic groups on HSA.
  • Analogs also include hydrocinnamate and cinnamate esters of polyhydric alcohols like pentaerythritol, for example, pentaerythritol esters with 3,2, and 1 acyl groups.
  • an acyl group is an ester group with a C 1-20 alkyl, C 2-20 alkenyl, 2-20 alkynyl, or C 6 or C 10 aryl moiety.
  • the compounds described herein all include at least one aryl ring, and each ring can, independently, be further substituted with one or more substituents, as defined herein.
  • substituents as defined herein.
  • substituents can provide useful properties in and of themselves or serve as a handle for further synthetic elaboration.
  • Benzene rings can be substituted using known chemistry, including the reactions discussed below.
  • alkyl substituents can be added using friedel craft alkylation reactions.
  • Biphenyl compounds can be synthesized by treating aryl phenylmagnesium bromides with copper salts, by the oxidative dehydrogenation of the aryl rings, or the dealkylation of toluene or other methyl-substituted aromatic rings.
  • Aryl rings can be nitrated, and the resulting nitro group on the aryl ring reacted with sodium nitrite to form a diazonium salt.
  • the diazonium salt can be manipulated using known chemistry to form various substituents on a benzene ring.
  • Diazonium salts can be halogenated using various known procedures, which vary depending on the particular halogen.
  • suitable reagents include bromine/water in concentrated HBr, thionyl chloride, pyr-ICl, fluorine and Amberlyst-A.
  • a number of other analogs, bearing substituents in the diazotized position, can be synthesized from the corresponding amino compounds, via the diazo intermediate.
  • the diazo compounds can be prepared using known chemistry, for example, as described above.
  • Nitro derivatives can be reduced to the amine compound by reaction with a nitrite salt, typically in the presence of an acid.
  • Other substituted analogs can be produced from diazonium salt intermediates, including, but are not limited to, hydroxy, alkoxy, fluoro, chloro, iodo, cyano, and mercapto, using general techniques known to those of skill in the art.
  • hydroxy-aromatic analogues can be prepared by reacting the diazonium salt intermediate with water.
  • Halogens on an aryl ring can be converted to Grignard or organolithium reagents, which in turn can be reacted with a suitable aldehyde or ketone to form alcohol-containing side chains.
  • alkoxy analogues can be made by reacting the diazo compounds with alcohols.
  • the diazo compounds can also be used to synthesize cyano or halo compounds, as will be known to those skilled in the art. Mercapto substitutions can be obtained using techniques described in Hoffman et al., J. Med. Chem. 36: 953 (1993).
  • the mercaptan so generated can, in turn, be converted to an alkylthio substitutent by reaction with sodium hydride and an appropriate alkyl bromide. Subsequent oxidation would then provide a sulfone.
  • Acylamido analogs of the aforementioned compounds can be prepared by reacting the corresponding amino compounds with an appropriate acid anhydride or acid chloride using techniques known to those skilled in the art of organic synthesis.
  • Hydroxy-substituted analogs can be used to prepare corresponding alkanoyloxy-substituted compounds by reaction with the appropriate acid, acid chloride, or acid anhydride.
  • the hydroxy compounds are precursors of both the aryloxy via nucleophilic aromatic substitution at electron deficient aromatic rings.
  • Ether derivatives can also be prepared from the hydroxy compounds by alkylation with alkyl halides and a suitable base or via Mitsunobu chemistry, in which a trialkyl- or triarylphosphine and diethyl azodicarboxylate are typically used. See Hughes, Org. React. (N.Y.) 42: 335 (1992) and Hughes, Org. Prep. Proced. Int. 28: 127 (1996) for typical Mitsunobu conditions.
  • Cyano-substituted analogs can be hydrolyzed to afford the corresponding carboxamido-substituted compounds. Further hydrolysis results in formation of the corresponding carboxylic acid-substituted analogs. Reduction of the cyano-sub stituted analogs with lithium aluminum hydride yields the corresponding aminomethyl analogs. Acyl-substituted analogs can be prepared from corresponding carboxylic acid-substituted analogs by reaction with an appropriate alkyllithium using techniques known to those skilled in the art of organic synthesis.
  • Carboxylic acid-substituted analogs can be converted to the corresponding esters by reaction with an appropriate alcohol and acid catalyst.
  • Compounds with an ester group can be reduced with sodium borohydride or lithium aluminum hydride to produce the corresponding hydroxymethyl-substituted analogs.
  • These analogs in turn can be converted to compounds bearing an ether moiety by reaction with sodium hydride and an appropriate alkyl halide, using conventional techniques.
  • the hydroxymethyl-substituted analogs can be reacted with tosyl chloride to provide the corresponding tosyloxymethyl analogs, which can be converted to the corresponding alkylaminoacyl analogs by sequential treatment with thionyl chloride and an appropriate alkylamine. Certain of these amides are known to readily undergo nucleophilic acyl substitution to produce ketones.
  • Hydroxy-substituted analogs can be used to prepare N-alkyl- or N-arylcarbamoyloxy-substituted compounds by reaction with N-alkyl- or N-arylisocyanates.
  • Amino-substituted analogs can be used to prepare alkoxycarboxamido-substituted compounds and urea derivatives by reaction with alkyl chloroformate esters and N-alkyl- or N-arylisocyanates, respectively, using techniques known to those skilled in the art of organic synthesis.
  • compositions and formulations described herein include proteasome inhibitor as described herein, a suitable carrier, and, optionally, one or more other active agents.
  • proteasome inhibitor used in the invention described herein can be in any suitable form that provides suitable bioavailability.
  • Drug delivery devices and formulations that locally deliver proteasome inhibitor to the eye are described in detail herein.
  • the disorders can be treated with an oral dosage form of the proteasome inhibitor.
  • Stabilized aqueous formulations comprising the proteasome inhibitors described herein can be prepared under strictly controlled Good Manufacturing Practice (GMP) conditions, ensuring both the quality and uniformity of the materials while avoiding the requirement for reconstitution by the pharmacist, physician, or patient. Moreover, sufficiently stable formulations are amendable to commercial transportation and can dispensed and administered without concern that the active component will be unacceptably degraded.
  • GMP Good Manufacturing Practice
  • suitably stable formulations can be dispensed for administration over an extended course of treatment, or packaged in single dose forms suitable for direct administration by a patient or physician without the effort or concern over reconstitution.
  • Stable aqueous formulations of the proteasome inhibitor can be administered topically.
  • the aqueous compositions preferably use water that has no physiologically or ophthalmically harmful constituents. Typically purified or deionized water is used.
  • the pH is adjusted by adding any physiologically and ophthalmically acceptable pH adjusting acids, bases, or buffers to within the range of about 5.0 to about 7.0, more preferably from about 5.8 to about 6.8, more preferably about 6.0 to about 6.5, more preferably at a pH of about 6.2 to about 6.4, more preferably about 6.25 to about 6.35, or more preferably about 6.3.
  • the proteasome inhibitor compositions of the present invention can be adjusted to a pH in the range of 5.0 to about 6.0, or more preferably about 5.5 to about 5.95, or more preferably 5.6 to 5.9. Any of the aforementioned ranges can be used with any of the compositions of the present invention, including, without limitation, intravenous and topical embodiments.
  • acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like
  • bases include potassium hydroxide, sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, THAM (tris-hydroxymethylamino-methane), and the like.
  • Salts and buffers include but are not limited to citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
  • the pH is preferably adjusted by adding sodium hydroxide.
  • the composition may be formulated for application as a liquid drop, ointment, a viscous solution or gel, a ribbon, or a solid.
  • the composition can be topically applied, for example, without limitation, to the front of the eye, under the upper eyelid, on the lower eyelid and in the cul-de-sac.
  • the stabilized formulation of proteasome inhibitor is formulated as a solid, semi-solid, powdered, or lyophilized composition, which upon addition of water or aqueous solutions produces a stabilized proteasome inhibitor formulation having a pH of about 4.0 to about 7.0, more preferably of about 5.8 to about 6.8, more preferably from about 6.0 to about 6.6, more preferably of about 6.2 to about 6.4, more preferably of about 6.25 to 6.35, and even more preferably about 6.3.
  • Topical administration eye drops or other suitable topical formulations for direct administration to the eye
  • subconjunctival injections periocular injections
  • intravitreal injections surgical implants
  • systemic routes Any of these routes can be used, as appropriate, depending on the particular disorder to be treated.
  • Intravitreal injections, periocular injections, and sustained-release implants can be used to achieve therapeutic levels of drugs in ocular tissues.
  • Eye drops are useful in treating conditions affecting either the exterior surface of the eye or tissues in the front of the eye, and some formulations can penetrate to the back of the eye for treatment of retinal diseases.
  • iontophoresis can be used to deliver the compounds described herein to the back of the eye.
  • the ocular iontophoresis system OcuPhorTM
  • Iontophoresis uses a small electrical current to transport ionized drugs into and through body tissues. Care must be taken not to use too high of a current density, which can damage eye tissues.
  • Iontophoresis typically involves using a drug applicator, a dispersive electrode, and an electronic iontophoresis dose controller.
  • the drug applicator can be a small silicone shell that contains a conductive element, such as silver-silver chloride.
  • a hydrogel pad can absorb the drug formulation.
  • a small, flexible wire can connect the conductive element to the dose controller.
  • the drug pad can be hydrated with a drug solution immediately before use, with the applicator is placed on the sclera of the eye under the lower eyelid. The eyelid holds the applicator in place during treatment.
  • the drug dose and rate of administration can be controlled by programming and setting the electronic controller.
  • Solid, semi-solid, powdered, or lyophilized composition may be prepared and packaged for single dose or multiple dose delivery.
  • the solid, semi-solid, powdered, or lyophilized compositions may also contain one or more additional medicaments or pharmaceutically acceptable excipients compatible with the intended route of administration.
  • the solid, semi-solid, powdered, or lyophilized compositions may also contain polymeric suspending agents.
  • the reconstitutable formulations of stabilized proteasome inhibitor thus provide for compositions having the advantages of a shelf life comparable to that of, and additionally, the extended shelf life of the stablized aqueous formulations described herein.
  • proteasome inhibitor compositions suitable for topical administration to the eye or periocular tissue can include one or more “ophthalmically acceptable carriers.” Such carriers are well known to those of skill in the art.
  • proteasome inhibitor can reach many of the tissues and fluids of the eye by oral administration, the proteasome inhibitors described herein are amenable to topical administration to eye and periocular tissues.
  • the proteasome inhibitor can be supplied to the eye surface in a variety of ways, including as an aqueous ophthalmic solution or suspension, as an ophthalmic ointment, and as an ocular insert, but application is not limited thereto.
  • any technique and ocular dosage form that supplies proteasome inhibitor to the external eye surface is included within the definition of “topically applying.”
  • the external surface of the eye is typically the outer layer of the conjunctiva, it is possible that the sclera, cornea, or other ocular tissue could be exposed such as by rotation of the eye or by surgical procedure, and thus be an external surface.
  • periocular tissues are defined as those tissues in contact with the lachrymal secretions, including the inner surface of the eye lid, the tissues of the orbit surrounding the eye, and the tissues and ducts of the lachrymal gland.
  • the amount of proteasome inhibitor topically supplied is effective to treat or prevent a disorder mediated by proteasomes, or associated with inflammation, in a tissue of the eye. More specifically, the concentration within the ocular tissue is desired to be at least about 0.25 ⁇ g/g, preferably at least about 1 ⁇ g/g, and more preferably at least about 10 ⁇ g/g.
  • the amount of proteasome inhibitor actually supplied to the external eye surface will almost always be higher than the tissue concentration. This reflects the penetration hold up of the proteasome inhibitor by the outer tissue layers of the eye and that penetration is, to some extent, concentration driven. Thus, supplying greater amounts to the exterior will drive more of the proteasome inhibitor into the tissues.
  • formulations as a depot will advantageously maintain the concentration of the proteasome inhibitor in the affected tissues for a period of at least about 2 hours, or more preferably at least about 4 hours, more preferably at least about 8 hours, or more preferably at least about 12 hours.
  • the stabilized proteasome inhibitor compositions of this invention may be topically administered to a variety of tissues, including the eye, to provide prophylaxis or treatment of ocular disorders mediated by proteasomes.
  • proteasome inhibitor is administered to eye tissues by intrascleral injection, as disclosed in U.S. Pat. Nos. 6,397,849 and 6,378,526.
  • Administration by means of intrascleral injection can advantageously be employed to provide the proteasome inhibitors described herein to the tissues of the posterior segment of the eye.
  • the proteasome inhibitor will (1) form a depot within the scleral layer and diffuse into the underlying tissue layers such as the choroid and/or retina, (2) be propelled through the scleral layer and into the underlying layers, or (3) a combination of both (1) and (2).
  • a preferred form of the present invention for topical ophthalmic administration provides for achieving a sufficiently high tissue concentration of proteasome inhibitor with a minimum of doses so that a simple dosing regimen can be used to treat or prevent the ocular disorders described herein.
  • a preferred technique involves forming or supplying a depot of proteasome inhibitor in contact with the external surface of the eye.
  • a depot refers to a source of proteasome inhibitor that is not rapidly removed by tears or other eye clearance mechanisms. This allows for continued, sustained high concentrations of proteasome inhibitor to be present in the fluid on the external surface of the eye by a single application.
  • absorption and penetration are dependent on both the dissolved drug concentration and the contact duration of the external tissue with the drug-containing fluid. As the drug is removed by clearance of the ocular fluid and/or absorption into the eye tissue, more drug is provided, e.g. dissolved, into the replenished ocular fluid from the depot.
  • the dosing regimen involves one to two doses per day over a one to three day period, more preferably one or two doses in a single day, to provide in vivo at least a 6 day treatment and more typically a 6 to 14 day treatment.
  • a depot can take a variety of forms so long as the proteasome inhibitor can be provided in sufficient concentration levels therein and is releasable therefrom, and that the depot is not readily removed from the eye.
  • a depot generally remains for at least about 30 minutes after administration, preferably at least 2 hours, and more preferably at least 4 hours.
  • the term “remains” means that neither the depot composition nor the proteasome inhibitor is exhausted or cleared from the surface of the eye prior to the indicated time. In some embodiments, the depot can remain for up to eight hours or more.
  • Typical ophthalmic depot forms include aqueous polymeric suspensions, ointments, and solid inserts. Polymeric suspensions are the most preferred form for the present invention and will be discussed subsequently.
  • Ointments which are essentially an oil-based delivery vehicle, are a well known compositions for topical administration.
  • Common bases for the preparation of ointments include mineral oil, petrolatum and combinations thereof, but oil bases are not limited thereto.
  • ointments When used for ophthalmic administration, ointments are usually applied as a ribbon onto the lower eyelid. The disadvantage of ointments is that they can be difficult to administer, can be messy, and can be uncomfortable or inconvenient to the patient. Moreover, temporarily blurred vision is a common difficulty encountered when they are employed for ophthalmic administration.
  • the matrix and active ingredient can be surrounded with a polymeric coating, such as in the sandwich structure of matrix/matrix+active/matrix, to further control release, as is well known in the art.
  • a polymeric coating such as in the sandwich structure of matrix/matrix+active/matrix
  • the kinds of polymers suitable for use as a matrix are well known in the art.
  • the proteasome inhibitor can be dispersed into the matrix material or dispersed amongst the monomer composition used to make the matrix material prior to polymerization.
  • the amount of proteasome inhibitor is generally from about 0.1 to 50%, more typically about 2 to 20%.
  • the insert can be placed, depending on the location and the mechanism used to hold the insert in position, by either the patient or the doctor, and is generally located under the upper eye lid. A variety of shapes and anchoring configurations are recognized in the art.
  • a biodegradable or bioerodible polymer matrix is used so that the spent insert does not have to be removed. As the biodegradable or bioerodible polymer is degraded or dissolved, the trapped proteasome inhibitor is released.
  • inserts can provide long term release and hence only a single application of the insert may be necessary, they are generally difficult to insert and are uncomfortable to the patient.
  • a preferred form of the stabilized proteasome inhibitor composition for administration of proteasome inhibitor to the ocular and periocular tissues is an aqueous polymeric suspension.
  • the proteasome inhibitor or the polymeric suspending agent is suspended in an aqueous medium having the properties as described above.
  • the proteasome inhibitor may be in suspension, although in the preferred pH ranges the proteasome inhibitor may also be in solution (water soluble), or both in solution and in suspension. It is possible for significant amounts of the proteasome inhibitor to be present in suspension.
  • the polymeric suspending agent is preferably in suspension (i.e. water insoluble and/or water swellable), although water soluble suspending agents are also suitable for use with a suspension of the proteasome inhibitor antibiotic.
  • the suspending agent serves to provide stability to the suspension and to increase the residence time of the dosage form on the eye. It can also enhance the sustained release of the drug in terms of both longer release times and a more uniform release curve.
  • polymeric suspending agents examples include dextrans, polyethylene glycols, polyvinylpyrolidone, polysaccharide gels, Gelrite®, cellulosic polymers like hydroxypropyl methylcellulose, and carboxy-containing polymers such as polymers or copolymers of acrylic acid, as well as other polymeric demulcents.
  • a preferred polymeric suspending agent is a water swellable, water insoluble polymer, especially a crosslinked carboxy-containing polymer.
  • Crosslinked carboxy-containing polymers used in practicing this invention are, in general, well known in the art.
  • such polymers may be prepared from at least about 90%, and preferably from about 95% to about 99.9% by weight, based on the total weight of monomers present, of one or more carboxy-containing monoethylenically unsaturated monomers (also occasionally referred to herein as carboxy-vinyl polymers).
  • Acrylic acid is the preferred carboxy-containing monoethylenically unsaturated monomer, but other unsaturated, polymerizable carboxy-containing monomers, such as methacrylic acid, ethacrylic acid, .beta.-methylacrylic acid (crotonic acid), cis-alpha-methylcrotonic acid (angelic acid), trans-alpha-methylcrotonic acid (tiglic acid), alpha-butylcrotonic acid, alpha-phenylacrylic acid, alpha-benzylacrylic acid, alpha-cyclohexylacrylic acid, .beta.-phenylacrylic acid (cinnamic acid), coumaric acid (o-hydroxycinnamic acid), umbellic acid (p-hydroxycoumaric acid), and the like can be used in addition to or instead of acrylic acid.
  • carboxy-containing monoethylenically unsaturated monomer but other unsaturated, polymerizable carboxy-containing monomers, such as methacrylic acid
  • Such polymers may be crosslinked by a polyfunctional crosslinking agent, preferably a difunctional crosslinking agent.
  • the amount of crosslinking should be sufficient to form insoluble polymer particles, but not so great as to unduly interfere with sustained release of the proteasome inhibitor antibiotic.
  • the polymers are only lightly crosslinked.
  • the crosslinking agent is contained in an amount of from about 0.01% to about 5%, preferably from about 0.1% to about 5.0%, and more preferably from about 0.2% to about 1%, based on the total weight of monomers present.
  • polyalkenyl polyether crosslinking agents containing two or more alkenyl ether groupings per molecule, preferably alkenyl ether groupings containing terminal H 2 C ⁇ C ⁇ groups, prepared by etherifying a polyhydric alcohol containing at least four carbon atoms and at least three hydroxyl groups with an alkenyl halide such as allyl bromide or the like, e.g., polyallyl sucrose, polyallyl pentaerythritol, or the like; see, e.g., Brown U.S. Pat. No. 2,798,053, the entire contents of which are incorporated herein by reference.
  • alkenyl halide such as allyl bromide or the like, e.g., polyallyl sucrose, polyallyl pentaerythritol, or the like; see, e.g., Brown U.S. Pat. No. 2,798,053, the entire contents of which are incorporated herein by reference.
  • Diolefinic non-hydrophilic macromeric crosslinking agents having molecular weights of from about 400 to about 8,000, such as insoluble di- and polyacrylates and methacrylates of diols and polyols, diisocyanate-hydroxyalkyl acrylate or methacrylate reaction products of isocyanate terminated prepolymers derived from polyester diols, polyether diols or polysiloxane diols with hydroxyalkylmethacrylates, and the like, can also be used as the crosslinking agents; see, e.g., Mueller et al. U.S. Pat. Nos. 4,192,827 and 4,136,250, the entire contents of each patent being incorporated herein by reference.
  • the crosslinked carboxy-vinyl polymers may be made from a carboxy-vinyl monomer or monomers as the sole monoethylenically unsaturated monomer present, together with a crosslinking agent or agents.
  • the polymers are ones in which up to about 40%, and preferably from about 0% to about 20% by weight, of the carboxy-containing monoethylenically unsaturated monomer or monomers has been replaced by one or more non-carboxyl-containing monoethylenically unsaturated monomer or monomers containing only physiologically and ophthalmically innocuous substituents, including acrylic and methacrylic acid esters such as methyl methacrylate, ethyl acrylate, butyl acrylate, 2-ethylhexylacrylate, octyl methacrylate, 2-hydroxyethyl-methacrylate, 3-hydroxypropylacrylate, and the like, vinyl acetate, N-vinylpyrrolidone, and the like;
  • the particles of crosslinked carboxy-vinyl polymer are monodisperse, meaning that they have a particle size distribution such that at least 80% of the particles fall within a 10 ⁇ m band of major particle size distribution. More preferably, at least 90% and most preferably at least 95%, of the particles fall within a 10 ⁇ m band of major particle size distribution.
  • a monodisperse particle size means that there is no more than 20%, preferably no more than 10%, and most preferably no more than 5% particles of a size below 1 ⁇ m. The use of a monodispersion of particles will give maximum viscosity and an increased eye residence time of the ophthalmic medicament delivery system for a given particle size. Monodisperse particles having a particle size of 30 ⁇ m and below are most preferred. Good particle packing is aided by a narrow particle size distribution.
  • the aqueous polymeric suspension normally contains proteasome inhibitor in an amount from about 0.05% to about 25%, preferably about 0.1% to about 20%, more preferably about 0.5% to about 15%, more preferably about 1% to about 12%, more preferably about 2% to about 10.0%, and polymeric suspending agent in an amount from about 0.05% to about 10%, preferably about 0.1% to about 5% and more preferably from about 0.2% to about 1.0% polymeric suspending agent.
  • another preferred amount of the polymeric suspending agent is an amount from about 0.5% to about 2.0%, preferably from about 0.5% to about 1.2%, and in certain embodiments from about 0.6% to about 0.9%, based on the weight of the composition.
  • the composition contains about 0.6% to about 0.8% of a polycarbophil such as NOVEON AA-1.
  • the amount of insoluble lightly crosslinked carboxy-vinyl polymer particles, the pH, and the osmotic pressure can be correlated with each other and with the degree of crosslinking to give a composition having a viscosity in the range of from about 500 to about 100,000 centipoise, and preferably from about 1,000 to about 30,000 or about 1,000 to about 10,000 centipoise, as measured at room temperature (about 25° C.) using a Brookfield Digital LVT Viscometer equipped with a number 25 spindle and a 13R small sample adapter at 12 rpm (Brookfield Engineering Laboratories Inc.; Middleboro, Mass.).
  • the viscosity is within the range of 500 to 3000 centipoise, it may be determined by a Brookfield Model DV-11+, choosing a number cp-52 spindle at 6 rpm.
  • the stabilized proteasome inhibitor formulations of the instant invention containing aqueous polymeric suspensions may be formulated so that they retain the same or substantially the same viscosity in the eye that they had prior to administration to the eye.
  • they may be formulated so that there is increased gelation upon contact with tear fluid.
  • a stabilized formulation containing DuraSite® or other similar polyacrylic acid-type polymer at a pH of about 5.8 to about 6.8, or more preferably about 6.0 to about 6.5, or more preferably at a pH of about 6.2 to about 6.4, or more preferably about 6.25 to about 6.35, or more preferably about 6.3 is administered to the eye
  • the polymer will swell upon contact with tear fluid which has a higher pH.
  • This gelation or increase in gelation leads to entrapment of the suspended proteasome inhibitor particles, thereby extending the residence time of the composition in the eye.
  • the proteasome inhibitor is released slowly as the suspended particles dissolve over time.
  • compositions advantageously combine stability and solubility characteristics of proteasome inhibitor, which display minimal degradation and relatively high solubility in aqueous compositions at the pre-administration pH, with the advantages of the gelling composition.
  • the viscous gels that result from fluid eye drops typically have residence times in the eye ranging from about 2 to about 12 hours, e.g., from about 3 to about 6 hours.
  • the agents contained in these drug delivery systems will be released from the gels at rates that depend on such factors as the drug itself and its physical form, the extent of drug loading and the pH of the system, as well as on any drug delivery adjuvants, such as ion exchange resins compatible with the ocular surface, which may also be present.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose
  • the tablets may be uncoated or they may be coated by known techniques, preferably to delay disintegration and absorption in the gastrointestinal tract until the tablets reach the colon.
  • the coating can be adapted to not release the proteasome inhibitor until after passage through the stomach, for example, by using an enteric coating (e.g., a pH-sensitive enteric polymer).
  • the solid tablet compositions may include a coating adapted to protect the composition from unwanted chemical changes (e.g., chemical degradation prior to the release of the active drug substance).
  • the coating may be applied on the solid dosage form in a similar manner as that described in Encyclopedia of Pharmaceutical Technology.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin). Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin.
  • Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
  • Controlled release compositions for oral use may be constructed to release the active drug by controlling the dissolution and/or the diffusion of the active drug sub stance.
  • controlled release is obtained by appropriate selection of various formulation parameters and ingredients, including, e.g., various types of controlled release compositions and coatings.
  • the drug is formulated with appropriate excipients into a pharmaceutical composition that, upon administration, releases the drug in a controlled manner. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. Additional examples include the formulations listed on the following websites: http://www.advancispharm.com/, http://www.intecpharma.com/, and www.depomedinc.com/
  • the matrix material may also include, e.g., hydrated metylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl inethacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.
  • compositions can also contain one or more of the following: surfactants, adjuvants including additional medicaments, buffers, antioxidants, tonicity adjusters, preservatives, thickeners or viscosity modifiers, and the like.
  • Additives in the formulation may desirably include sodium chloride, EDTA (disodium edetate), and/or BAK (benzalkonium chloride), sorbic acid, methyl paraben, propyl paraben, and chlorhexidine.
  • BAK benzalkonium chloride
  • Other excipients compatible with various routes of adminsitration such as topical and parenteral administration are outlined in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 18.sup.th edition (1990).
  • a further aspect of the present invention involves the above-mentioned use of additional active agents in combination with the proteasome inhibitor.
  • a composition comprising proteasome inhibitor, an additional active agent, and an ophthalmically acceptable carrier can advantageously simplify administration and allow for treating or preventing multiple conditions or symptoms simultaneously.
  • additional medicaments which can be present in any of the ophthalmic compositional forms described herein including fluid and solid forms, are pharmaceutically active compounds having efficacy in ocular application and which are compatible with proteasome inhibitor and with the eye.
  • the additional medicaments include anti-inflammatory agents including steroidal and non-steroidal anti-inflammatories, anti-allergic agents, antivirals, antifungals, and anesthetics. These other medicaments are generally present in a therapeutically effective amount. These amounts are generally within the range of from about 0.01 to 5%, more typically 0.1 to 2%, for fluid compositions and typically from 0.5 to 50% for solid dosage forms.
  • anesthetics used in ocular surgeries include tetracaine, lidocaine, marcaine, oxybuprocaine, benzocaine, butamben, dibucaine, pramoxine, proparacaine, proxymetacaine, cocaine, and Alpha-2 adrenergic receptor agonists such as Dexmedetomidine and Propofol.
  • Steroids are one of the most commonly used medications for decreasing ocular inflammation. By inhibiting the breakdown of phospholipids into arachidonic acid, these agents act early on the inflammatory pathway. The most common side effects of this class of medications are cataract formation and glaucoma.
  • Representative anti-inflammatory agents used for ophthalmic indications include dexamethasone, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, medrysone, triamcinolone, rimexolone, and pharmaceutically-acceptable salts thereof.
  • non-steroidal anti-inflammatory agents used in ophthalmic indications include Acular, Acular LS, Acuvail, Bromday, bromfenac, diclofenac, flurbiprofen, Ilevro, ketorolac, nepafenac, Nevanac, Ocufen, Prolensa, and Voltaren.
  • proteasome inhibitor can be advantageous to co-administer with one or more anti-inflammatory agents.
  • One such combination includes both proteasome inhibitor and dexamethasone, which can be administered in the form of a suspension, or in the form of eye drops, for topical application.
  • Another representative corticosteroid is loteprednol etabonate.
  • the combination therapy can be extremely useful in connection with steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where bacterial infection or a risk of bacterial ocular infection exists.
  • Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe, where the inherent risk of steroid use in certain infective conjunctivitis is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies.
  • a combination drug product that includes a proteasome inhibitor and an anti-inflammatory agent is indicated where the risk of inflammation is high.
  • Steroids are one of the most commonly used medications for decreasing ocular inflammation. By inhibiting the breakdown of phospholipids into arachidonic acid, these agents act early on the inflammatory pathway. The most common side effects of this class of medications are cataract formation and glaucoma. Drugs such as loteprednol etabonate (Lotemax; Bausch+Lomb, Rochester, N.Y.) carry a lower risk of increased TOP. Another new agent is difluprednate (Durezol; Sirion Therapeutics, Tampa, Fla.), which possesses even greater potency than the other available corticosteroids.
  • nonsteroidal anti-inflammatory drugs have been used to treat inflammatory conditions, physicians should exercise caution when prescribing this class of medications.
  • corneal melting Isawi and Dhaliwal, “Corneal melting and perforation in Stevens Johnson syndrome following topical bromfenac use,” J Cataract Refract Surg. 2007; 33(9):1644-1646).
  • cyclosporine 0.05% Restasis; Allergan, Inc., Irvine, Calif.
  • combinations of a proteasome inhibitor and cyclosporine particularly in the form of ocular formulations such as eye drops, are also within the scope of the invention.
  • autologous serum tears can be very effective. Because they contain several important components of natural tears such as epidermal growth factor, fibronectin, and vitamin A, autologous serum tears increase the health of the ocular surface (Kojima, et al., Autologous serum eye drops for the treatment of dry eye diseases, Cornea, 27(suppl 1):S25-30 (2008)).
  • proteasome inhibitors described herein can be administered before, during, or after administration of an antimicrobial agent, and an antimicrobial compound can be included in the proteasome inhibitor-containing compositions.
  • the antimicrobials include antibiotics, antivirals, and antifungals.
  • antibiotics include beta-lactams such as penicillins (e.g., penicillin G, penicillin V, methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin, ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, piperacillin, azlocillin, and temocillin), cephalosporins (e.g., cepalothin, cephapirin, cephradine, cephaloridine, cefazolin, cefamandole, cefuroxime, cephalexin, cefprozil, cefaclor, loracarbef, cefoxitin, cefmatozole, cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefpodoxime, ceftibuten, cefdinir, cefpirome, ce
  • antibiotics can be used in the dose ranges currently known and used for these agents, particularly when such are prescribed for treating ocular disorders.
  • Different concentrations may be employed depending on the clinical condition of the patient, the goal of therapy (treatment or prophylaxis), the anticipated duration, and the severity of the infection for which the drug is being administered. Additional considerations in dose selection include the type of infection, age of the patient (e.g., pediatric, adult, or geriatric), general health, and co-morbidity. Determining what concentrations to employ are within the skills of the pharmacist, medicinal chemist, or medical practitioner. Typical dosages and frequencies are provided, e.g., in the Merck Manual of Diagnosis & Therapy (17th Ed. M H Beers et al., Merck & Co.).
  • proteasome inhibitors described herein are suitable for use in treating ocular disorders mediated by proteasomes, and ocular disorders associated with inflammation, including those resulting from a bacterial, viral or fungal infection.
  • ocular disorders have an inflammatory component, and thus can be treated or prevented using the proteasome inhibitors described herein.
  • Representative types of inflammatory ocular disorders that can be treated using the proteasome inhibitors described herein, for example, by topical application of compositions including one or more proteasome inhibitor, and also optionally including an anti-inflammatory agent include ocular rosacea, wet and dry age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, neovascular glaucoma, retinal vasculitis, uveitis, such as posterior uveitis, keratoconjunctivitis sicca, conjunctivitis, retinitis secondary to glaucoma, neovascular glaucoma, episcleritis, scleritis, optic neuritis, retrobulbar neuritis, ocular inflammation following ocular surgery, ocular inflammation resulting from physical eye trauma, Pterygium (Surfer'
  • the ocular disorder to be treated or prevented is ocular rosacea.
  • Ocular rosacea is a manifestation of rosacea that affects the eyes and eyelids. Signs and symptoms generally consist of redness, irritation or burning of the eyes. Affected individuals may also feel that there is something, such as an eyelash, in the eye and frequently have redness of the nose and cheeks as well.
  • ocular rosacea may result from reactions of the sclera, limbus and cornea to staphylococcal endotoxins or cell-mediated hypersensitivity responses to staphylococcal antigens.
  • the variability in response of patients with ocular rosacea to these immune reactions may account for the extreme variability in clinical signs and symptoms associated with this disorder.
  • Conventional therapy for ocular rosacea includes normalizing tear film disturbances, typically with warm compresses, punctal occlusion (temporary or permanent) if aqueous tear production is deficient, using artificial tears to help provide ocular surface wetting, controlling bacterial overgrowth, including keeping the eyelids clean, using topical antibiotics to reduce bacterial flora, particularly when acute mucopurulent blepharoconjunctivitis, marginal corneal infiltrates or peripheral ulcerative keratitis are present, and controlling inflammatory and hypersensitivity reactions, for example, using topical corticosteroids, including topical progestational steroids such as compounded medroxyprogesterone (typically at around a 1% concentration by weight).
  • topical corticosteroids including topical progestational steroids such as compounded medroxyprogesterone (typically at around a 1% concentration by weight).
  • proteasome inhibitors can be combined with treatment using proteasome inhibitors.
  • a proteasome inhibitor can be added to an artificial tears formulation, and a steroid and/or an antibiotic can also be added.
  • Macular degeneration is the leading cause of severe vision loss in people over age 60. It occurs when the small central portion of the retina, known as the macula, deteriorates. The retina is the light-sensing nerve tissue at the back of the eye. Because the disease develops as a person ages, it is often referred to as age-related macular degeneration (AMD). Although macular degeneration is almost never a totally blinding condition, it can be a source of significant visual disability.
  • AMD age-related macular degeneration
  • Dry form The “dry” form of macular degeneration is characterized by the presence of yellow deposits, called drusen, in the macula. A few small drusen may not cause changes in vision; however, as they grow in size and increase in number, they may lead to a dimming or distortion of vision that people find most noticeable when they read. In more advanced stages of dry macular degeneration, there is also a thinning of the light-sensitive layer of cells in the macula leading to atrophy, or tissue death. In the atrophic form of dry macular degeneration, patients may have blind spots in the center of their vision. In the advanced stages, patients lose central vision.
  • wet form The “wet” form of macular degeneration is characterized by the growth of abnormal blood vessels from the choroid underneath the macula. This is called choroidal neovascularization. These blood vessels leak blood and fluid into the retina, causing distortion of vision that makes straight lines look wavy, as well as blind spots and loss of central vision. These abnormal blood vessels eventually scar, leading to permanent loss of central vision.
  • ocular disorder associated with inflammation is noninfectious anterior uveitis.
  • This disorder is typically treated using corticosteroids such as prednisolone acetate (0.125% and 1% by weight), Betamethasone (1% by weight), Dexamethasone sodium phosphate (0.1% by weight in eye drops, 0.05% by weight in ointment form), Fluorometholone (0.1% and 0.25% by weight, or 0.1% in ointment form), Loteprednol, and Rimexolone (1% by weight).
  • corticosteroids such as prednisolone acetate (0.125% and 1% by weight), Betamethasone (1% by weight), Dexamethasone sodium phosphate (0.1% by weight in eye drops, 0.05% by weight in ointment form), Fluorometholone (0.1% and 0.25% by weight, or 0.1% in ointment form), Loteprednol, and Rimexolone (
  • Topical non-steroidal anti-inflammatory drugs like flubriprofen can also be used.
  • Certain ocular disorders have a microbial component, including viruses, bacteria, fungi, and parasites.
  • proteasome inhibitor formulations of this invention can be used, along with an appropriate antimicrobial agent, to treat or prevent a variety of conditions associated with ocular infection.
  • the role of the proteasome inhibitor in this setting is to minimize damage associated with inflammation, while the antimicrobial agent is administered to address the underlying cause of the inflammation (i.e., the microbial infection).
  • conditions of the eyelids including blepharitis, blepharconjunctivies, meibomianitis, acute or chronic hordeolum, chalazion, dacryocystitis, dacryoadenities, and acne rosacea; conditions of the conjunctiva, including conjunctivitis, ophthalmia neonatorum, and trachoma; conditions of the cornea, including corneal ulcers, superficial and interstitial keratitis, keratoconjunctivitis, foreign bodies, and post operative infections; and conditions of the anterior chamber and uvea, including endophthalmitis, infectious uveitis, and post operative infections, are a few of the tissues and conditions that can be treated by topical application of the proteasome inhibitor and the antimicrobial agent.
  • the prevention of infection includes pre-operative treatment prior to surgery as well as other suspected infectious conditions or contact.
  • prophylaxis situations include treatment prior to surgical procedures such as blepharoplasty, removal of chalazia, tarsorrhapy, procedures for the canualiculi and lacrimal drainage system and other operative procedures involving the lids and lacrimal apparatus; conjunctival surgery including removal of ptyregia, pingueculae and tumors, conjunctival transplantation, traumatic lesions such as cuts, burns and abrasions, and conjunctival flaps; corneal surgery including removal of foreign bodies, keratotomy, and corneal transplants; refractive surgery including photorefractive procedures; glaucoma surgery including filtering blebs; paracentesis of the anterior chamber; iridectomy; cataract surgery; retinal surgery; and procedures involving the extraocular muscles.
  • the prevention of ophthalmia neonatorum is also included.
  • compositions described herein including a proteasome inhibitor and an appropriate antimicrobial agent specific for the type of microbial infection, can be used to treat or prevent an ocular infection, and to prevent, minimize, or treat inflammation resulting from an ocular infection.
  • Specific indications that can be treated or prevented include conditions of the eyelids, including blepharitis, blepharconjunctivies, meibomianitis, acute or chronic hordeolum, chalazion, dacryocystitis, dacryoadenities, and acne rosacea; conditions of the conjunctiva, including conjunctivitis, ophthalmia neonatorum, and trachoma; conditions of the cornea, including corneal ulcers, superficial and interstitial keratitis, keratoconjunctivitis, foreign bodies, and post operative infections; and conditions of the anterior chamber and uvea, including endophthalmitis, infectious uveitis, and post operative infections.
  • the prevention of infection includes pre-operative treatment prior to surgery as well as other suspected infectious conditions or contact.
  • prophylaxis situations include treatment prior to surgical procedures such as blepharoplasty, removal of chalazia, tarsorrhapy, procedures for the canualiculi and lacrimal drainage system and other operative procedures involving the lids and lacrimal apparatus; conjunctival surgery including removal of ptyregia, pingueculae and tumors, conjunctival transplantation, traumatic lesions such as cuts, burns and abrasions, and conjunctival flaps; corneal surgery including removal of foreign bodies, keratotomy, and corneal transplants; refractive surgery including photorefractive procedures; glaucoma surgery including filtering blebs; paracentesis of the anterior chamber; iridectomy; cataract surgery; retinal surgery; and procedures involving the extraocular muscles.
  • the prevention of ophthalmia neonatorum is also included.
  • Representative microbial species include one or more of the following organisms: Staphylococcus including Staphylococcus aureus and Staphylococcus epidermidis; Streptococcus including Streptococcus pneumoniae and Streptococcus pyogenes as well as Streptococci of Groups C, F, and G and Viridans group of Streptococci; Haemophilus influenza including biotype III (H.
  • Aegyptius Haemophilus ducreyi; Moraxella catarrhalis; Neisseria including Neisseria gonorrhoeae and Neisseria meningitidis; Chlamydia including Chlamydia trachomatis, Chlamydia psittaci , and Chlamydia pneumoniae; Mycobacterium including Mycobacterium tuberculosis and Mycobacterium avium -intracellular complex as well as a typical mycobacterium including M. marinum, M. fortuitm , and M.
  • compositions include, but are not limited to, the following:
  • Trachomatis is an infectious eye disease, and the leading cause of the world's infectious blindness. Globally, 84 million people suffer from active infection and nearly 8 million people are visually impaired as a result of this disease.
  • Trachoma is caused by Chlamydia trachomatis and it is spread by direct contact with eye, nose, and throat secretions from affected individuals, or contact with fomites (inanimate objects), such as towels and/or washcloths, that have had similar contact with these secretions. Flies can also be a route of mechanical transmission. Untreated, repeated trachoma infections result in entropion—a painful form of permanent blindness when the eyelids turn inward, causing the eyelashes to scratch the cornea.
  • the bacterium has an incubation period of 5 to 12 days, after which the affected individual experiences symptoms of conjunctivitis, or irritation similar to “pink eye.” Blinding endemic trachoma results from multiple episodes of re-infection that maintains the intense inflammation in the conjunctiva. Without re-infection, the inflammation will gradually subside.
  • the conjunctival inflammation is called “active trachoma” and usually is seen in children, especially pre-school children. It is characterized by white lumps in the undersurface of the upper eye lid (conjunctival follicles or lymphoid germinal centers) and by non-specific inflammation and thickening often associated with papillae. Follicles may also appear at the junction of the cornea and the sclera (limbal follicles). Active trachoma will often be irritating and have a watery discharge. Bacterial secondary infection may occur and cause a purulent discharge.
  • trachoma The later structural changes of trachoma are referred to as “cicatricial trachoma”. These include scarring in the eye lid (tarsal conjunctiva) that leads to distortion of the eye lid with buckling of the lid (tarsus) so the lashes rub on the eye (trichiasis). These lashes will lead to corneal opacities and scarring, and then to blindness.
  • compositions described herein can be used prophylactically to prevent the spread of infection, and/or to prevent the onset of symptoms associated with inflammation.
  • Prophylactic administration can be used, for example, in poor communities where infection has already occurred, and is likely to spread.
  • Bacterial conjunctivitis is a purulent infection of the conjunctiva by any of several species of gram-negative, gram-positive, or acid-fast organisms. Some of the more commonly found genera causing conjunctival infections are Haemophilus, Streptococcus, Neisseria , and Chlamydia.
  • Hordeolum is a purulent infection of one of the sebaceous glands of Zeis along the eyelid margin (external) or of the meibomian gland on the conjunctival side of the eyelid (internal).
  • Infectious keratoconjunctivitis is an infectious disease of cattle, sheep, and goats, characterized by blepharospasm, lacrimation, conjunctivitis, and varying degrees of corneal opacity and ulceration.
  • the causative agent is Moraxella bovis ; in sheep, mycoplasma, rickettsia, Chlamydia , or acholeplasma, and in goats, rickettsia.
  • Ocular tuberculosis is an infection of the eye, primarily the iris, ciliary body, and choroid.
  • Uveitis is the inflammatory process that involves the uvea or middle layers of the eye.
  • the uvea includes the iris (the colored part of the eye), the choroid (the middle blood vessel layer) and the ciliary body—the part of the eye that joins both parts.
  • Uveitis is the eye's version of arthritis. The most common symptoms and signs are redness in the white part of the eye, sensitivity to light, blurry vision, floaters, and irregular pupil. Uveitis can present at any age, including during childhood.
  • Suppurative uveitis is an intraocular infection caused mainly by pus-producing bacteria, and rarely by fungi.
  • the infection may be caused by an injury or surgical wound (exogenous) or by endogenous septic emboli in such diseases as bacterial endocarditis or meningococcemia.
  • Nonspecific conjunctivitis has many potential causes, including fatigue and strain, environmental dryness and pollutants, wind and dust, temperature and radiation, poor vision correction, contact lens use, computer use and dry eye syndrome. Another cause relates to the body's innate reaction to dead cells, which can cause nonspecific conjunctivitis.
  • This type of infection can occur when a patient's lid disease causes mild conjunctivitis, and dead Staphylococcal bacteria from the lids fall onto the ocular surface.
  • the cells trigger an inflammatory hypersensitivity reaction on the already irritated eyes.
  • This inflammatory reaction against the dead cells can be treated using the proteasome inhibitors described herein, optionally in combination with another anti-inflammatory agent, to combat inflammation, and an antibacterial compound to address the underlying cause of the inflammation, namely, infection by living Staph bacteria.
  • NSC patients can benefit from a combination treatment (active agents and an anti-inflammatory agent) to battle inflammatory NSC.
  • Corneal inflammation is one of the most common ocular diseases in both humans and animals and can lead to blindness or even cause lost of the eye itself.
  • keratitis is classified into infectious and non-infectious, while in veterinary medicine the tradition is to classify keratitis rather into ulcerative and non-ulcerative (Whitley and Gilger 1999).
  • Non-ulcerative keratitis in dogs is usually caused by mechanical irritation (pigmentary keratitis) or by immune-mediated process (pannus).
  • non-ulcerative infectious keratitis also exists (corneal abscess, mycotic, viral keratitis).
  • Ulcerative keratitis can be of non-infectious (recurrent erosions, traumatically induced superficial ulceration) or infectious (bacterial, viral, mycotic) origin. Even in the cases of originally non-infectious ulceration, after disruption in the epithelium secondary infection often occurs.
  • OLM ocular larva migrans
  • Cysticercosis is a parasitic infestation of different body organs by Cysticercosis cellulosae . Ocular manifestations of malaria and leishmaniasis are well documented and sight threatening conditions.
  • These and other ocular parasitic infections can be treated by using the compounds described herein to treat the inflammation, and treating the underlying disorder with an appropriate anti-parasitic agent.
  • a patient may suffer from ocular inflammation.
  • Administration of a proteasome inhibitor as described herein, before, during, and/or after eye surgery, can minimize, prevent, or treat the inflammation.
  • Representative eye surgeries for which administration of proteasome inhibitors can be used include, but are not limited to, the following.
  • Laser eye surgery can be used to treat non-refractive conditions (for example, to seal a retinal tear), while radial keratotomy is an example of refractive surgery that can be performed without using a laser.
  • Laser eye surgery or laser corneal sculpting, is a medical procedure that uses a laser to reshape the surface of the eye to improve or correct myopia (short-sightedness), hypermetropia (long sightedness) and astigmatism (uneven curvature of the eye's surface).
  • Refractive surgery aims to correct errors of refraction in the eye, reducing or eliminating the need for corrective lenses. Also, limbal relaxing incisions (LRI) can be used to correct minor astigmatism.
  • LRI limbal relaxing incisions
  • Keratoplasty is defined as surgery performed upon the cornea, such as a corneal transplantation/grafting.
  • Keratotomy is a type of refractive surgical procedure, and can refer to radial keratotomy or photorefractive keratotomy.
  • AK astigmatic keratotomy
  • RK radial keratotomy
  • M.A.R.K. Mini Asymmetric Radial Keratotomy
  • HK hexagonal keratotomy
  • Keratomilleusis is a method of reshaping the cornea surface to change its optical power.
  • a disc of cornea is shaved off, quickly frozen, lathe-ground, then returned to its original power.
  • a variation of this type of operation is laser-assisted in-situ keratomileusis (LASIK), including laser-assisted sub-epithelial keratomileusis (LASEK), also known as Epi-LASIK.
  • Similar procedures include IntraLASIK, automated lamellar keratoplasty (ALK), photorefractive keratectomy (PRK), laser thermal keratoplasty (LTK), and conductive keratoplasty (CK), which uses radio frequency waves to shrink corneal collagen and is used to treat mild to moderate hyperopia.
  • a cataract is an opacification or cloudiness of the eye's crystalline lens that prevents light from forming a clear image on the retina. If visual loss is significant, surgical removal of the lens may be warranted, with lost optical power usually replaced with a plastic intraocular lens (IOL).
  • IOL plastic intraocular lens
  • Glaucoma is a group of diseases affecting the optic nerve that results in vision loss and is frequently characterized by raised intraocular pressure (TOP).
  • TOP raised intraocular pressure
  • Canaloplasty enhances drainage through the eye's natural drainage system to provide sustained reduction of intra-ocular pressure (TOP).
  • Canaloplasty uses microcatheter technology to create a tiny incision to gain access to a canal in the eye.
  • the microcatheter circumnavigates the canal around the iris, enlarging the main drainage channel and its smaller collector channels through the injection of a sterile, gel-like material called viscoelastic.
  • the catheter is then removed and a suture is placed within the canal and tightened. By opening up the canal, the pressure inside the eye can be reduced.
  • a Karmra inlay is placed inside the cornea, and has a small aperture that gives clearer vision at intermediate and near distances.
  • Scleral reinforcement surgery is used to mitigate degenerative myopia.
  • Corneal surgery includes most refractive surgery, as well as corneal transplant surgery, penetrating keratoplasty (PK), keratoprosthesis (KPro), phototherapeutic keratectomy (PTK), pterygium excision, corneal tattooing, and osteo-odonto-keratoprosthesis (OOKP), in which support for an artificial cornea is created from a tooth and its surrounding jawbone.
  • PK penetrating keratoplasty
  • KPro keratoprosthesis
  • PTK phototherapeutic keratectomy
  • OLKP osteo-odonto-keratoprosthesis
  • Vitreo-retinal surgery includes vitrectomies, including anterior vitrectomy, which removes the front portion of vitreous tissue to prevent or treat vitreous loss during cataract or corneal surgery, or to remove misplaced vitreous in conditions such as aphakia pupillary block glaucoma.
  • Pars plana vitrectomy or trans pars plana vitrectomy (TPPV) removes vitreous opacities and membranes through a pars plana incision, and is frequently combined with other intraocular procedures for the treatment of giant retinal tears, tractional retinal detachments, and posterior vitreous detachments.
  • Pan retinal photocoagulation is a type of photocoagulation therapy used in the treatment of diabetic retinopathy.
  • a scleral buckle is often used to repair a retinal detachment to indent or “buckle” the sclera inward, usually by sewing a piece of preserved sclera or silicone rubber to its surface.
  • Laser photocoagulation, or photocoagulation therapy involves using a laser to seal a retinal tear.
  • Retinal cryopexy or retinal cryotherapy, is a procedure that uses intense cold to induce a chorioretinal scar and to destroy retinal or choroidal tissue.
  • Eye muscle surgery typically corrects strabismus and includes transposition/repositioning procedures, tightening/strengthening procedures, loosening/weakening procedures, advancement (moving an eye muscle from its original place of attachment on the eyeball to a more forward position), recession (moving the insertion of a muscle posteriorly towards its origin), myectomy, myotomy, tenectomy, tenotomy, resection, tucking, isolating the inferior rectus muscle, and disinserting the medial rectus muscle.
  • Adjustable suture surgery involves reattaching an extraocular muscle using a stitch that can be shortened or lengthened within the first post-operative day, to obtain better ocular alignment.
  • a dacryocystorhinostomy (DCR) or dacryocystorhinotomy restores the flow of tears into the nose from the lacrimal sac when the nasolacrimal duct does not function.
  • Canaliculodacryocystostomy is a surgical correction for a congenitally blocked tear duct in which the closed segment is excised and the open end is joined to the lacrimal sac.
  • Canaliculotomy involves slitting of the lacrimal punctum and canaliculus for the relief of epiphora.
  • a dacryoadenectomy is the surgical removal of a lacrimal gland.
  • a dacryocystectomy is the surgical removal of a part of the lacrimal sac.
  • a dacryocystostomy is an incision into the lacrimal sac, usually to promote drainage.
  • a dacryocystotomy is an incision into the lacrimal sac.
  • Eye removal includes enucleation, which involves removing the eye, leaving the eye muscles and remaining orbital contents intact, evisceration, which involves removing the eye's contents, leaving the scleral shell intact (usually performed to reduce pain in a blind eye), and exenteration, which involves removing the entire orbital contents, including the eye, extraocular muscles, fat, and connective tissues (usually performed to remove malignant orbital tumors).
  • Additional surgeries include posterior sclerotomy, in which an opening is made into the vitreous through the sclera, as for detached retina or the removal of a foreign body, macular hole repair, partial lamellar sclerouvectomy, partial lamellar sclerocyclochoroidectomy, partial lamellar sclerochoroidectomy, radial optic neurotomy, macular translocation surgery, through 360 degree retinotomy, and through scleral imbrication technique.
  • Epikeratophakia is the removal of the corneal epithelium and replacement with a lathe cut corneal button.
  • Implants can be inserted, including intracorneal rings (ICRs), corneal ring segments (Intacs), implantable contact lenses, and scleral expansion bands (SEB).
  • ICRs intracorneal rings
  • Intacs corneal ring segments
  • SEB scleral expansion bands
  • Presbyopia is a condition where, with age, the eye exhibits a progressively diminished ability to focus on near objects. Presbyopia can be reversed surgically, including through anterior ciliary sclerotomy (ACS), and laser reversal of presbyopia (LRP).
  • ACS anterior ciliary sclerotomy
  • LRP laser reversal of presbyopia
  • a ciliarotomy is a surgical division of the ciliary zone in the treatment of glaucoma.
  • a ciliectomy is 1) the surgical removal of part of the ciliary body, or 2) the surgical removal of part of a margin of an eyelid containing the roots of the eyelashes.
  • a ciliotomy is a surgical section of the ciliary nerves.
  • a conjunctivoanstrostomy is an opening made from the inferior conjuctival cul-de-sac into the maxillary sinus for the treatment of epiphora.
  • Conjuctivoplasty is plastic surgery of the conjunctiva.
  • a conjunctivorhinostomy is a surgical correction of the total obstruction of a lacrimal canaliculus by which the conjuctiva is anastomosed with the nasal cavity to improve tear flow.
  • a correctomedialysis, or coretomedialysis is an excision of a small portion of the iris at its junction with the ciliary body to form an artificial pupil.
  • a corectomy, or coretomy is any surgical cutting operation on the iris at the pupil.
  • a corelysis is a surgical detachment of adhesions of the iris to the capsule of the crystalline lens or cornea.
  • a coremorphosis is the surgical formation of an artificial pupil.
  • a coreplasty, or coreoplasty, is plastic surgery of the iris, usually for the formation of an artificial pupil.
  • a coreoplasy, or laser pupillomydriasis is any procedure that changes the size or shape of the pupil.
  • a cyclectomy is an excision of portion of the ciliary body.
  • a cyclotomy, or cyclicotomy is a surgical incision of the ciliary body, usually for the relief of glaucoma.
  • a cycloanemization is a surgical obliteration of the long ciliary arteries in the treatment of glaucoma.
  • An iridectomesodialsys is the formation of an artificial pupil by detaching and excising a portion of the iris at its periphery.
  • An iridodialysis is a localized separation or tearing away of the iris from its attachment to the ciliary body.
  • An iridencleisis is a surgical procedure for glaucoma in which a portion of the iris is incised and incarcerated in a limbal incision.
  • An iridesis is a surgical procedure in which a portion of the iris is brought through and incarcerated in a corneal incision in order to reposition the pupil.
  • An iridocorneosclerectomy is the surgical removal of a portion of the iris, the cornea, and the sclera.
  • An iridocyclectomy is the surgical removal of the iris and the ciliary body.
  • An iridocystectomy is the surgical removal of a portion of the iris to form an artificial pupil.
  • An iridosclerectomy is the surgical removal of a portion of the sclera and a portion of the iris in the region of the limbus for the treatment of glaucoma.
  • An iridosclerotomy is the surgical puncture of the sclera and the margin of the iris for the treatment of glaucoma.
  • a rhinommectomy is the surgical removal of a portion of the internal canthus.
  • a trepanotrabeculectomy is used to treat chronic open and chronic closed angle glaucoma.
  • any and all of the disorders discussed above can be treated using the proteasome inhibitors described herein, alone or in combination with other active agents, such as anti-inflammatory agents, antimicrobials, and anesthetics, using appropriate compositions as described herein.
  • Hydroxypropylmethyl cellulose, sodium chloride, edetate sodium (EDTA), BAK and surfactant are dissolved in a beaker containing approximately 1 ⁇ 3 of the final weight of water and stirred for 10 minutes with an overhead stirring.
  • Proteasome inhibitor is added and stirred to disperse for 30 minutes.
  • the solution is sterilized by autoclaving at 121° C. for 20 minutes.
  • the proteasome inhibitor may be dry heat sterilized and added by aseptic powder addition after sterilization.
  • Mannitol, Poloxamer 407, and boric acid are dissolved separately in approximately 1 ⁇ 2 of the final weight of water and added by sterile filtration (0.22 ⁇ m filter) and stirred for 10 minutes to form a mixture.
  • the mixture is adjusted to the desired pH in the range of 5.8 to 7.0 with sterile sodium hydroxide (1N to 10N) while stirring, brought to a final weight with sterile water, and aseptically transferred to multi-dose containers.
  • Noveon AA-1 an acrylic acid polymer available from B. F. Goodrich, is slowly dispensed into a beaker containing approximately 1 ⁇ 3 of the final weight of water and stirred for 1.5 hrs. with an overhead stirrer. Ethylene diamine tetra acetic acid (EDTA), benzalkonium chloride (BAK), sodium chloride, and surfactant are then added to the polymer solution and stirred for 10 minutes after each addition. The polymer suspension is at a pH of about 3.0-3.5. The proteasome inhibitor is added and stirred to disperse for 30 minutes. The pH of the mixture is titrated to the desired pH in the range of 5.8 to 6.8, and brought to final weight/volume with water.
  • EDTA Ethylene diamine tetra acetic acid
  • BAK benzalkonium chloride
  • sodium chloride sodium chloride
  • surfactant surfactant
  • the mixture is aliquoted into single or multiple dose containers, which are sterilized by autoclaving at 121° C., for 20 minutes.
  • the proteasome inhibitor may be dry heat sterilized and added by aseptic powder addition after sterilization.
  • Noveon AA-1 is slowly dispensed into a beaker containing approximately 1 ⁇ 3 of the final weight of water and stirred for 1.5 hrs., with overhead stirring, to form a Noveon suspension.
  • the Noveon suspension is sterilized by autoclaving at 121° C., for 20 minutes.
  • Solutions containing mannitol and boric acid, or solutions containing Dequest® (a brand of bisphosphonate), mannitol, and boric acid are dissolved separately in approximately 1 ⁇ 2 of the final weight of water, added to the sterilized Noveon polymer suspension by sterile filtration (0.22 ⁇ m filter), and stirred for 10 minutes.
  • the dry heat sterilized proteasome inhibitor is then added by aseptic powder addition.
  • the mixture is adjusted to the desired pH with sterile sodium hydroxide (1N to 10N) while stirring, brought to final weight with sterile water, and aseptically filled into multi-dose containers.
  • Noveon AA-1 is slowly dispensed into a beaker containing approximately 1 ⁇ 2 of the final weight of water and stirred for 1.5 hrs., with overhead stirring.
  • Edetate sodium (EDTA) Poloxamer 407 (a hydrophilic non-ionic surfactant of the more general class of copolymers known as poloxamers, specifically, a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol, with approximate lengths of the two PEG blocks of 101 repeat units, and an approximate length of the propylene glycol block of 56 repeat units), and sodium chloride are then added to the polymer suspension and stirred for 10 minutes.
  • EDTA Edetate sodium
  • Poloxamer 407 a hydrophilic non-ionic surfactant of the more general class of copolymers known as poloxamers, specifically, a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol
  • the polymer suspension is at a pH of about 3.0-3.5.
  • the proteasome inhibitor is added and stirred to disperse for 30 minutes.
  • the mixture is adjusted to desired pH with sodium hydroxide (1N to 10N) while stirring, and is sterilized by autoclaving at 121° C. for 20 minutes.
  • the proteasome inhibitor may be dry heat sterilized and added by aseptic powder addition after sterilization. Mannitol is dissolved in 1/10 of the final weight of water and sterile filtered (0.22 ⁇ m filter) in to the polymer suspension and stirred for 10 minutes.
  • the mixture is adjusted to desired pH with sterile sodium hydroxide (1N to 10N) while stirring, brought to final weight with sterile water, and aseptically filled into unit-dose containers.
  • a proteasome inhibitor ointment is prepared by dissolving 0.3 grams of proteasome inhibitor in a mixture containing 3.0 grams mineral oil/96.2 grams white petrolatum by stirring in a 100 ml beaker while heating sufficiently to dissolve both compounds.
  • the mixture is sterile filtered through a 0.22 ⁇ m filter at a sufficient temperature to be filtered and filled aseptically into sterile ophthalmic ointment tubes.
  • HPMC Hydroxypropylmethyl cellulose
  • sodium chloride sodium chloride
  • EDTA sodium sodium, and surfactant
  • HPMC Hydroxypropylmethyl cellulose
  • the mixture is sterilized by autoclaving at 121° C., for 20 minutes.
  • a proteasome inhibitor and a steroid are dry heat sterilized and added to the HPMC-containing solution by aseptic powder addition.
  • Mannitol, Poloxamer 407, BAK, and boric acid are dissolved separately in approximately 1 ⁇ 2 of the final weight of water and added by sterile filtration (0.22 um filter) and stirred for 10 minutes to form a mixture.
  • the mixture is adjusted to the desired pH with sterile sodium hydroxide (1N to 10N) while stirring, brought to a final weight with sterile water, and aseptically dispensed into multi-dose containers.
  • Noveon AA-1 is slowly dispersed into a beaker containing approximately 1 ⁇ 3 of the final weight of water and stirred for 1.5 hrs., with an overhead stirrer. EDTA, sodium chloride, and surfactant are then added to the polymer solution and stirred for 10 minutes after each addition.
  • the polymer suspension is at a pH of about 3.0-3.5.
  • the mixture is sterilized by autoclaving at 121° C. for 20 minutes.
  • the proteasome inhibitor and steroid, as indicated in table 2 are dry heat sterilized and added to the polymer suspension by aseptic powder addition.
  • BAK, mannitol, and boric acid are dissolved separately in approximately 1 ⁇ 2 of the final weight of water, added to the polymer mixture by sterile filtration (0.22 um filter) and stirred for 10 minutes.
  • the mixture is adjusted to the desired pH with sterile sodium hydroxide (1N to 10N) while stirring, brought to a final weight with sterile water, and aseptically dispensed into multi-dose containers.

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US20230050398A1 (en) * 2021-08-04 2023-02-16 Harrow Ip, Llc Methods for increasing shelf-life of ophthalmic pharmaceutical compositions
US11471475B1 (en) 2022-03-08 2022-10-18 Ralph P. Stone Ophthalmic suspension vehicles and related methods for pharmaceutical ingredient delivery
US11679079B1 (en) 2022-03-08 2023-06-20 EternaTear, Inc. Ophthalmic formulations and related methods
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US11752167B1 (en) 2022-03-08 2023-09-12 Timothy R. Willis Ophthalmic suspension vehicles and related methods for pharmaceutical ingredient delivery
US11771714B1 (en) 2022-03-08 2023-10-03 Ralph P. Stone Ophthalmic suspension vehicles and related methods for pharmaceutical ingredient delivery
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JP2018533629A (ja) 2018-11-15
WO2017078953A1 (en) 2017-05-11
CA3004587A1 (en) 2017-05-11
EP3370709A1 (en) 2018-09-12
IL259153A (en) 2018-06-28
CN108883081A (zh) 2018-11-23
EP3370709A4 (en) 2019-12-18

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